Examples of pain secondary to damage to a peripheral nerve are causalgia and phantom limb pain. Causalgia may develop after traumatic damage to a peripheral nerve. Even though evoked pain is reduced, severe pain may develop in the area innervated by the damaged nerve. This pain may be very difficult to treat, even with strong analgesic drugs. The pain is caused in part by spontaneous activity that develops in dorsal root ganglion cells; such activity may be attributed to upregulation of Na+ channels. In some cases the pain seems to be maintained by sympathetic neural activity, because a sympathetic nerve block may alleviate the pain. Sympathetic involvement may relate to the sprouting of damaged sympathic postganglionic axons into the dorsal root ganglia, and it may be accompanied by upregulation of adrenoreceptors in primary afferent neurons. Phantom limb pain follows traumatic amputation in some individuals. Such phantom pain is clearly not caused by activation of nociceptors in the area in which pain is felt, because these receptors are no longer present.
Lesions of the thalamus or at other levels of the spinothalamocortical pathway may cause central pain, which is a severe spontaneous pain. However, interruption of the nociceptive pathway by the same lesion may simultaneously prevent or reduce the pain evoked by peripheral stimulation. The mechanism of such trauma-induced pain caused by neural damage is poorly understood. The pain appears to depend on changes in the activity and response properties of more distant neurons in the nociceptive system.
Transduction in the Somatosensory System
Unraveling the transduction processes for the somatosensory system has proven difficult because of a variety of factors. The heart of the transduction process occurs at the specialized endings of the peripheral branch of the axon of the sensory neuron (dorsal root ganglia and trigeminal ganglia cells). These endings have channels that are activated by mechanical, thermal, and/or chemical stimuli and that allow the current flow that underlies the local generator potential (see
Fig. 5.13 ). The generator potential then triggers spikes in the afferent fiber (see
Fig. 5.14 ). However, the fact is that somatosensory axons are found throughout the body at low densities, making purification of the proteins difficult (e.g., compare with the retina, in which photoreceptors are packed at high density onto a small surface).
Complicating matters, the generator potential can be modified by a host of voltage-gated channels, both excitatory (e.g., Na+ and Ca++ channels) and inhibitory (K+ channels). Moreover, as described earlier, in many cases the axon terminal is encapsulated (e.g., Pacinian corpuscles), and the properties of this accessory structure modify the transduction process. They may do so passively, as a result of the mechanical characteristics of the capsule, or actively by having the accessory cells release transmitter in response to a stimulus. An example of the latter is Merkel cells, where recent evidence suggests the Merkel cells and the axon innervating them both have mechanosensitive channels and the Merkel cells release neurotransmitter.
Despite these complications, using a number of approaches, our knowledge of somatosensory transduction processes has begun to increase rapidly.
Until recently, ASIC (acid-sensing ion channel) proteins, which belong to the DEG/ENaC family, had been thought to be the channel proteins underlying the cutaneous mechanoactivated currents, because homologs of these proteins underlie the touch sensation in invertebrates such as Caenorhabditis elegans, and because some ASIC proteins are highly expressed in dorsal root ganglion cells. However, the mechanoactivated currents in dorsal root ganglion cells are not affected by knockdown of the ASIC proteins, indicating that they are not the channel underlying cutaneous mechanotransduction. Nevertheless, touch and pain sensitivity is altered in such knockdown mutants, so they may still play a modulatory role in the transduction process.